Korean J Thorac Cardiovasc Surg 2015;48:335-344 ISSN: 2233-601X (Print)

□ Clinical Research □

http://dx.doi.org/10.5090/kjtcs.2015.48.5.335

ISSN: 2093-6516 (Online)

The Significance of Serum Carcinoembryonic Antigen in Lung Adenocarcinoma Jae Jun Kim, M.D.1, Kwanyong Hyun, M.D.2, Jae Kil Park, M.D.2, Seok Whan Moon, M.D.3

Background: A raised carcinoembryonic antigen (CEA) may be associated with significant pathology during the postoperative follow-up of lung adenocarcinoma. Methods: We reviewed the medical records of 305 patients who underwent surgical resections for primary lung adenocarcinoma at a single institution between April 2006 and February 2013. Results: Preoperative CEA levels were significantly associated with age, smoking history, pathologic stage including pT (pathologic tumor stge), pN (pathologic nodal stage) and overall pathological stage, tumor size and differentiation, pathologically positive total lymph node, N1 and N2 lymph node, N2 nodal station (0/1/2=1.83/2.94/7.21 ng/mL, p=0.019), and 5-year disease-free survival (0.591 in group with normal preoperative CEA levels vs. 0.40 in group with high preoperative CEA levels, p=0.001). Preoperative CEA levels were significantly higher than postoperative CEA levels (p＜0.001, Wilcoxon signed-rank test). Postoperative CEA level was also significantly associated with disease-free survival (p＜0.001). A follow-up serum CEA value of ＞2.57 ng/mL was found to be the appropriate cutoff value for the prediction of cancer recurrence with sensitivity and specificity of 71.4% and 72.3%, respectively. Twenty percent of patients who had recurrence of disease had a CEA level elevated above this cutoff value prior to radiographic evidence of recurrence. Postoperative CEA, pathologic stage, differentiation, vascular invasion, and neoadjuvant therapy were identified as independent predictors of 5-year disease-free survival in a multivariate analysis. Conclusion: The follow-up CEA level can be a useful tool for detecting early recurrence undetected by postoperative imaging studies. The perioperative follow-up CEA levels may be helpful for providing personalized evaluation of lung adenocarcinoma. Key words: 1. Lung adenocarcinoma 2. Carcinoembryonic antigen 3. Prognosis

section for non-small cell lung cancer varies for each in-

INTRODUCTION

dividual [1,2]. Therefore, personalized evaluation and manageLung cancer is one of the leading causes of death, and ad-

ment for non-small cell lung cancer is essential, and in-

enocarcinoma has been reported to be the most common sub-

formation on other factors as well as the pathologic stage is

type of lung cancer [1]. Despite having the same cell type

necessary to evaluate the current status and to predict the ac-

and pathologic stages, the clinical prognosis after surgical re-

curate prognosis [3-5]. One such factor can be serum carci-

1

Department of Thoracic and Cardiovascular Surgery, Uijeongbu St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Department of Thoracic and Cardiovascular Surgery, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, 3 Department of Thoracic and Cardiovascular Surgery, St. Paul’s Hospital, The Catholic University of Korea College of Medicine Received: September 25, 2014, Revised: December 4, 2014, Accepted: December 5, 2014, Published online: October 5, 2015 Corresponding author: Jae Kil Park, Department of Thoracic and Cardiovascular Surgery, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea (Tel) 82-2-2258-2858 (Fax) 82-2-594-8644 (E-mail) [email protected] C The Korean Society for Thoracic and Cardiovascular Surgery. 2015. All right reserved. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 2

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Jae Jun Kim, et al

noembryonic antigen (CEA) [2,6]. The serum CEA level has

routinely performed with chest X-ray, chest computed tomog-

been widely used as a tumor marker and as a predictor of

raphy (CT), and positron emission tomography (PET), brain

disease progression or recurrence in various types of cancer,

magnetic resonance imaging (MRI), or bone scan (as needed).

particularly in colorectal cancer [7,8]. Further, some studies

The clinical and pathologic stages were determined according

have proposed the possibility of the CEA level as a tumor

to the American Joint Committee on Cancer tumor-node-

marker or as a predictor after surgical resection for early

metastasis staging method (7th edition). The postoperative

non-small cell lung cancer [2,9]. However, the National

follow-up consisted of chest X-ray every 3 months, chest CT,

Comprehensive Cancer Network (NCCN) guidelines for

PET-CT, and brain MRI (as needed) every 6 months for 5

non-small cell lung cancer do not include serum CEA for the

years post-surgery. The preoperative and follow-up CEA lev-

evaluation and management of non-small cell lung cancer.

els were measured using the chemiluminescent enzyme im-

When the preoperative or follow-up CEA level exceeds the

munoassay technique. All laboratory tests were carried out by

normal range, the evaluation and management of these pa-

standard methods, using an auto-analyzer (Hitachi 7600-210;

tients tend to be same as those of patients with a normal

Hitachi, Tokyo, Japan) and commercially available assay kits

CEA level. The purpose of the present study is to clarify the

(Sekisui Medical Co. Ltd., Tokyo, Japan). The normal refer-

significance of the perioperative serum CEA level in predict-

ence value used for our laboratory was a CEA level of 3 ng/mL.

ing the clinical course (i.e., recurrence or metastasis) of a pa-

A serum CEA level of less than 3 ng/mL was defined as

tient with lung adenocarcinoma. We retrospectively compiled

normal, and follow-up CEA levels were taken every 3 or 6

the preoperative and follow-up serum CEA levels in all cases

months. Because there was no definite policy or algorithm for

of surgical pulmonary resection. These CEA levels were ana-

the measurement of the CEA level, we defined each CEA

lyzed along with the resulting pathologies and the subsequent

level strictly according to time. The serum CEA level within

clinical courses.

1 month before surgery was defined as ‘preoperative CEA’ and the serum CEA level within 5 months after surgery was defined as ‘postoperative CEA.’ The serum CEA level within

METHODS

6 months before recurrence was defined as ‘CEA before

1) Materials and methods

recurrence.’ The serum CEA level at the last follow-up was

We reviewed the medical records of 305 patients who un-

defined as ‘last CEA.’ If there were more than two CEA lev-

derwent surgical resection for primary adenocarcinoma lung

els in the same period, we chose the higher level. Neoad-

cancer at Seoul Saint Mary’s Hospital between April 2006

juvant or adjuvant therapy was performed by following the

and February 2013. Because there was no definite policy or

NCCN guidelines with consideration of the patient condition.

algorithm for the measurement of the serum CEA level, some

The clinicopathologic data including imaging studies, serum

of the patients did not have a record of their preoperative or

CEA level, surgical procedure, pathology and mutation stud-

follow-up CEA level. The remainder, 158 of 305 patients,

ies (EGFR and k-ras), and clinical prognosis were analyzed.

had records of both preoperative and follow-up CEA. The in-

Since most patients were in the early lung cancer stage, the

clusion criteria were primary lung adenocarcinoma, pre-

number of cancer-related deaths was small, and various fac-

operative and follow-up serum CEA levels, and curative and

tors after recurrence could influence the overall survival, we

complete resection including intended limited resection. The

carried out a 5-year disease-free survival (DFS, also referred

exclusion criteria were secondary primary lung cancer cases,

to as recurrence-free survival) study instead of an overall sur-

salvage or palliative cases, and epidermal growth factor re-

vival study by using recurrence as a primary endpoint to clar-

ceptor tyrosine inhibitor (EGFR TKI) intake for adjuvant

ify the significance of the serum CEA level. Any recurrence

therapy cases. Intended limited resection (wedge resection or

or death due to any cause was included in the recurrence-free

segmentectomy) was performed in high-risk patients at a clin-

survival. Note that DFS is interchangeable with recurrence-

ically early stage. Preoperative evaluations for staging were

free survival under this study design of following up on post

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Carcinoembryonic Antigen in Lung Cancer

Table 1. Overall clinicopathologic characteristics of the patients (N=158) Characteristic Age (yr) Gender Male Female Combined other cancers No Yes Pathologic stage IA IB IIA IIB IIIA Extent of resection Wedge resection Segmentectomy Lobectomy Bilobectomy Preoperative serum carcinoembryonic antigen level (ng/mL) Normal High Differentiation Good Moderate Poor Status of follow-up Dead Alive or follow-up loss Recurrence No or follow-up loss Yes Epidermal growth factor receptor mutation No Yes Not measured k-ras mutation No Yes Not measured Neoadjuvant therapy No Yes Adjuvant therapy No Yes

stage; differentiation; pleural, vascular, and lymphatic invasion; and neoadjuvant or adjuvant therapy. The approval from the

Value

institutional review board of Seoul St. Mary's Hospital was

64.5

obtained for the present study (IRB approval number: 81 (51.3) 77 (48.7)

KC13RISI0290). 2) Statistical analysis

128 (81.0) 30 (19.0) 94 35 12 3 14

Since our data did not have a normal distribution, all data were analyzed using nonparametric statistical methods. The

(59.5) (22.2) (7.6) (1.9) (8.9)

comparisons among subgroups were evaluated using the Mann-Whitney U test, Wilcoxon’s signed-rank test, or the Jonckheere-Terpstra test. Association studies were evaluated using Spearman’s rho test. DFS rates were calculated using

19 (12.0) 1 (0.6) 135 (85.4) 3 (1.9) 1.88

the Kaplan-Meier method, and comparisons of survival curves were carried out by using the log-rank test. To determine the independent prognostic factors of survival, a multivariate analysis was conducted using the Cox proportional hazards

113 (71.5) 45 (28.5)

model (backward stepwise method). Recurrence or metastasis

81 (51.3) 64 (40.5) 13 (8.2)

PASW SPSS computer software program ver. 18.0 (SPSS Inc.,

was defined as an event. The results were analyzed using the Chicago, IL, USA). A p-value of less than 0.05 was considered statistically significant.

16 (10.1) 142 (89.9)

RESULTS

103 (65.2) 55 (34.8)

1) Clinicopathologic characteristics

There were 158 patients (81 male and 77 female) who underwent complete resections or intended limited resections;

37 (23.4) 41 (25.9) 80 (50.6)

their median age was 64.5 years (range, 33 to 85 years). Among these 158 patients, 6 (3.8%) patients received neo-

64 (40.5) 15 (9.5) 79 (50.0)

adjuvant therapy and 36 patients (22.8%) received adjuvant

152 (96.2) 6 (3.8)

of cancer, such as adenosquamous carcinoma and mucinous

therapy. All patients were pathologically diagnosed with adenocarcinoma or adenocarcinoma combined with another type adenocarcinoma. The differentiation grades varied as follows: well, 81 (51.3%); moderate, 64 (40.5%); and poor, 13 (8.2%).

122 (77.2) 36 (22.8)

The pathologic stages were as follows: IA, 94 (59.5%); IB, 35 (22.1%); IIA, 12 (7.6%); IIB, 3 (1.9%); and IIIA, 14

Values are presented as number of patients (%) or median.

(8.9%). The overall clinicopathologic characteristics of these operative patients with lung cancer. The parameters associated

patients are summarized in Table 1.

with DFS included age; gender; mutation study (EGFR and k-ras mutation); extent of resection; CEA levels; pathologic − 337 −

Jae Jun Kim, et al

Fig. 1. Preoperative serum carcinoembryonic antigen (CEA) levels according to the pathologic stage. Preoperative CEA levels were positively associated with the overall pathologic stage (p=0.001). In addition, there were more patients in the high preoperative CEA group than in the normal preoperative CEA group at the relatively high pathologic stages (p=0.017, Fisher’s exact test).

Fig. 2. Disease-free survival (i.e., recurrence-free survival) according to preoperative carcinoembryonic antigen (CEA) levels. DFS of the normal preoperative CEA group is significantly higher than that of the high preoperative CEA group (p=0.001, log-rank test).

operative CEA level was significantly higher than that of patients with a high preoperative CEA level (0.591 vs. 0.40;

2) Preoperative carcinoembryonic antigen levels

p=0.001; log-rank test) (Fig. 2). The results of a univariate anal-

The incidence of patients with high preoperative CEA lev-

ysis of preoperative CEA are summarized in Table 2.

els was 28.5%. Along with the low incidence of a high pre-

3) Postoperative carcinoembryonic antigen levels

operative CEA level, we found that the preoperative CEA levels were significantly associated with age; smoking history;

The incidence of patients with a high postoperative CEA

pathologic stage including pathologic tumor (pT), pathologic

level was 16.5%. There was no significant relationship between

nodal (pN) stage, and overall pathologic stage (IA, IB, IIA,

postoperative CEA levels and the overall pathologic stage

IIB, and IIIA); tumor size; tumor grading (differentiation of

(p=0.062, Jonckheere-Terpstra test) (Fig. 3). However, the highest

cancer cells); number of pathologically positive total lymph

postoperative CEA level had a positive association with the

nodes, N1 lymph nodes, N2 lymph nodes, and N2 nodal sta-

pathologic stage (p=0.008, Jonckheere-Terpstra test). Postoper-

tions; and DFS rate. Preoperative CEA levels of smokers

ative CEA levels in patients with recurrent disease were sig-

were higher than those of non-smokers (1.44 vs. 2.40 ng/mL;

nificantly higher than the follow-up CEA levels in disease-

p=0.010; Mann-Whitney U test). Preoperative CEA levels

free patients (p=0.002, Mann–Whitney U test). Further, the

were positively associated with age (p=0.009, Spearman’s rho

patient group with a normal postoperative CEA level had a

test), pT stage, pN stage, and the overall pathologic stage (p

longer disease-free interval than the patient group with a high

＜0.001, p=0.023, and p=0.001, respectively; Jonckheere-

postoperative CEA level (p＜0.001, log-rank test) (Fig. 4).

Terpstra test) (Fig. 1), tumor size (p=0.001, Spearman’s rho

4) Relationship between preoperative and postoperative

test), pathologically positive total lymph nodes (p=0.007,

carcinoembryonic antigen levels

Spearman’s rho test), pathologically positive N1 and N2 lymph nodes (p=0.040 and p=0.017, respectively; Spearman’s

Preoperative CEA levels were positively associated with

rho test), pathologically positive N2 lymph nodal stations

postoperative CEA levels (correlation coefficient=0.789; p＜

(p=0.019, Jonckheere–Terpstra test), and poorer differentiation

0.001; Spearman’s rho test). Preoperative CEA levels were

well/moderate/poor=1.59/2.20/2.26 ng/mL; p=0.003; Jonckheere–

significantly higher than postoperative CEA levels (1.88 vs.

Terpstra test). The DFS of patients with a normal pre-

1.46 ng/mL; p＜0.001; Wilcoxon’s signed-rank test). However,

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Carcinoembryonic Antigen in Lung Cancer

Table 2. Results of a univariate analysis of preoperative CEA levels Variable Age Gender Combined with another cancer Smoking Overall pathologic stage Pathologic tumor stage Tumor size Pathologic nodal stage Pathologically positive LN Pathologically positive N1 LN Pathologically positive N2 LN Pathologically positive N2 nodal station Differentiation Pleural invasion Vascular invasion Lymphatic invasion Epidermal growth factor receptor mutation k-ras mutation Disease-free interval

Relationship Positive correlation Not associated Not associated Preoperative CEA levels of smokers were higher than those of non-smokers. Positive correlation Positive correlation Positive correlation Positive correlation Positive correlation Positive correlation Positive correlation Positive correlation Negative correlation Not associated Not associated Not associated Not associated Not associated Disease-free interval of the normal preoperative CEA group was longer than that of the high preoperative CEA group

p-value 0.009 0.684 0.597 0.010 0.001 ＜0.001 0.001 0.023 0.007 0.040 0.017 0.019 0.003 0.148 0.061 0.148 0.988 0.375 0.001

CEA, serum carcinoembryonic antigen; LN, lymph node.

Fig. 3. Postoperative carcinoembryonic antigen (CEA) levels according to pathologic stage. There was no significant relationship between postoperative CEA levels and the overall pathologic stage (p=0.062). In addition, there was no relationship between the postoperative CEA groups (normal and high) and the overall pathologic stage.

Fig. 4. DFS according to postoperative carcinoembryonic antigen (CEA) levels. The disease-free interval in the patient group with a normal postoperative CEA level is significantly longer than that in the patient group with a high postoperative CEA level (p＜0.001, log-rank test). 5) Receiver operating characteristic analysis of follow-up carcinoembryonic antigen levels

the difference between the preoperative and the postoperative CEA levels was not associated with the disease-free interval.

The cutoff CEA value from the Receiver operating charac-

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Jae Jun Kim, et al

teristic (ROC) curve analysis of serum CEA to predict cancer recurrence is shown in Fig. 5. For the purpose of screening, a follow-up serum CEA value of ＞2.57 ng/mL was found to be the appropriate cutoff value for the prediction of cancer recurrence with a sensitivity of 71.4% and a specificity of 72.3%. We determined the cutoff value that provided the likelihood ratios and the sensitivity and specificity values that had the greatest clinical value in the screening of lung cancer recurrence, and we chose a higher sensitivity at the cost of lower specificity. The area under the ROC curve was 0.752 (95% confidence interval [CI], 0.650–0.854; p＜0.001), which indicated the potential predictive value of cancer recurrence. 6) Follow-up carcinoembryonic antigen levels in groups with high or normal preoperative carcinoembryonic antigen levels

Fig. 5. Cutoff carcinoembryonic antigen (CEA) values to predict cancer recurrence or metastasis. A follow-up serum CEA value of ＞2.57 ng/mL seems to be the appropriate cutoff level for the prediction of cancer recurrence or metastasis with a sensitivity of 71.4% and a specificity of 72.3%.

The group with high preoperative CEA levels had signifi8) Univariate and multivariate prognostic analyses for

cantly higher follow-up CEA levels than the other group with

5-year disease-free survival

normal preoperative CEA levels in both recurrent and disease-free cases (p＜0.001; p=0.001; Mann-Whitney U test). In addition, the ROC curve analysis of the serum CEA level in the group with high preoperative CEA levels showed the appropriate cutoff value (＞4.18 ng/mL) for the prediction of cancer recurrence or metastasis with a sensitivity of 85.0% and a specificity of 83.3% with an area of 0.901 (95% CI, 0.806–0.997), which suggests that follow-up postoperative CEA levels can be used as a potential predictive value for cancer recurrence or metastasis even in patients with high preoperative CEA levels.

The mean follow-up period of the present study was 35.5 months (range, 5 to 88 months), and the overall 5-year DFS rate for the cases was 52.8%. Radiographic evaluations revealed that there was recurrence or metastasis in 55 patients (34.8%) during the follow-up and that 16 patients (10.1%) died of cancer-related causes. The 5-year DFS rate in the univariate analysis was associated with pre- and postoperative CEA levels; pathologic stage; differentiation; pleural, vascular, and lymphatic invasion; and neoadjuvant and adjuvant therapy. However, age, gender, EGFR and k-ras mutation,

7) Follow-up carcinoembryonic antigen levels in patients with or without recurrent disease

and extent of resection were not associated with 5-year DFS after surgical resection (since we began measuring EGFR and k-ras mutation after 2010, the effects of EGFR and k-ras mu-

Patients with recurrent disease had significantly higher fol-

tation on 5-year DFS could not be analyzed completely be-

low-up CEA levels at the time of recurrence than the dis-

cause of the short duration of observation). There was no

ease-free patients (p＜0.001, Mann-Whitney U test). Further,

DFS difference between wedge resection and anatomic re-

the follow-up CEA levels at recurrence were significantly higher

section, nor limited resection (wedge and segmentectomy) and

than the follow-up CEA levels before recurrence in the same

more extended resections. In contrast to our expectations, ne-

patient (p＜0.001, Wilcoxon’s signed-rank test). We found that

oadjuvant and adjuvant therapy had negative prognostic ef-

20% of the patients who had disease recurrence had an ele-

fects on the 5-year DFS rate. The results of a univariate anal-

vated CEA level above the suggested cutoff value (＞2.57

ysis based on the 5-year DFS rate are shown in Table 3. All

ng/mL) prior to the radiographic evidence of recurrence.

variables found to be significant in the univariate analysis of − 340 −

Carcinoembryonic Antigen in Lung Cancer

Table 3. Univariate analysis for 5-year DFS Variable Age (yr) ≤65 ＞65 Gender Male Female Preoperative CEA level (ng/mL) ≤3.0 ＞3.0 Postoperative CEA level (ng/mL) ≤3.0 ＞3.0 Pathologic stage IA IB IIA IIB IIIA Pleural invasion No Yes Vascular invasion No Yes Lymphatic invasion No Yes Epidermal growth factor receptor mutation (4-year DFS) No Yes k-ras mutation (5-year DFS) No Yes Differentiation Good Other (moderate and poor) Extent of resection Wedge resection Segmentectomy or greater resection Neoadjuvant therapy No Yes Adjuvant therapy No Yes

5-year DFS (%)

Table 4. Multivariate analyses for 5-year DFS p-value

Variable

0.380

Pathologic stage IA IB IIA IIB IIIA Preoperative CEA High (＞3 ng/mL) Postoperative CEA High (＞3 ng/mL) Pleural invasion Yes Vascular invasion Yes Lymphatic invasion Yes Differentiation Neoadjuvant therapy Yes Adjuvant therapy Yes

54.7 55.5 0.237 55.1 55.8 0.001 62.6 40.2 ＜0.001

59.6 35.9 ＜0.001

66.0 57.6 33.8 0.00 17.9 0.003 60.8 31.3 0.001 57.7 40.4

Hazard ratio

p-value

0.817 2.659 6.530 2.623

0.001 0.613 0.024 0.003 0.029 0.732

2.168

0.032 0.211

3.485

0.004

2.253

0.748 0.011

4.722

0.004 0.690

DFS, disease-free survival; CEA, serum carcinoembryonic antigen.

＜0.001

62.1 25.5 0.117

the 5-year DFS in the multivariate analysis. The results of the multivariate analysis based on the 5-year DFS rate are shown

24.5 53.4

in Table 4.

0.182 19.7 34.2

DISCUSSION

＜0.001

70.0 34.6

Despite having the same cell type and pathologic stages, 0.085

the clinical prognosis after surgical resection for non-small

41.2 53.7

cell lung cancer varies for each individual [1,2]. This may be ＜0.001

due to inaccurate or insufficient evaluation, and heterogeneous

57.9 0.00

characteristics of the patients with the same stage of disease. We routinely evaluate the preoperative cancer staging and the

＜0.001

66.1 0.00

postoperative status through imaging studies, such as chest CT and PET-CT. However, there may be unidentified or missed

DFS, disease-free survival; CEA, serum carcinoembryonic antigen.

metastases. Even if the staging is correct, the patients’ heterogeneity in the same stage can result in unexpected recurrence

the 5-year DFS were included as covariates for the multi-

or metastases. Therefore, we need modalities for additional

variate analysis, and accordingly, postoperative CEA levels,

evaluation to improve the prognosis of these patients [10,11].

pathologic stage, differentiation, vascular invasion, and neo-

One modality can be the serum CEA levels [2,6]. Serum

adjuvant therapy were identified as independent predictors of

CEA is one of the most widely used markers in various can-

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Jae Jun Kim, et al

cers, particularly in the case of colorectal cancer [7,8]. The

[4,13,14]. Similarly, the present study showed that the post-

possibility of using serum CEA levels as a tumor marker or

operative CEA levels, the pathologic stage, differentiation,

a predictor has been reported after the surgical resection of

vascular invasion, and neoadjuvant therapy were the prog-

early non-small cell lung cancer [6,9]. Our study showed that

nostic factors of the 5-year DFS in the multivariate analysis.

the pre- and postoperative and follow-up CEA levels are

We tentatively suggest that the CEA levels, including the pre-

strongly associated with the current status and prognosis of

operative and follow-up CEA levels, should be included in

patients in all surgical stages following surgical resection.

the NCCN guidelines for more appropriate decision making

The preoperative CEA levels were generally higher with more

and management. Patients with relatively high preoperative or

progressive cancer before surgery. Patients with higher pre-

follow-up CEA levels need to be evaluated and managed

operative CEA levels had a significantly shorter 5-year DFS

more carefully, even in patients with stage IA or IB disease

than those with normal preoperative CEA levels. There was a

[6,14]. After the completion of adjuvant therapy without any

significant decrease in the CEA level after surgery, which can

detection of recurrence or metastasis by imaging studies, ad-

reflect the reduction or disappearance of the cancer load and

ditional management may be needed if a patient has elevated

extent. Patients with higher postoperative CEA levels also

follow-up CEA levels [9,10]. A number of previous studies

had a significantly shorter 5-year DFS than patients with nor-

have reported that the serum CEA level was closely asso-

mal postoperative CEA levels, which can suggest the possi-

ciated with EGFR or k-ras mutation [7,15,16]. However, our

bility of the cancer remaining after surgery in patients with

study found no association between these factors. In contrast

relatively high postoperative CEA levels [12]. The follow-up

to our expectations, neoadjuvant therapy had a negative prog-

CEA level at recurrence was significantly higher than both

nostic effect on the 5-year DFS in the multivariate analysis,

the CEA level before recurrence in the same patient and the

which may be due to the small sample size, and on patients

median follow-up CEA level in the disease-free patients.

having more advanced disease, and led to poor prognosis in

Therefore, this may suggest that the possibility of recurrence

patients who required neoadjuvant therapy. The extent of re-

or metastasis may exist in asymptomatic, average-risk patients

section had no effect on the 5-year DFS, which may be due

with an elevated follow-up CEA level. In addition, we found

to the patients undergoing limited resection at the early

that 20% of the patients who had recurrence of disease had

stages, and having less invasive disease and a good prognosis.

an elevated CEA level prior to the radiographic evidence of

This study has several limitations. The first is its retro-

recurrence, which suggests the possibility that CEA may pro-

spective design. The second limitation is the small sample

vide earlier detection of recurrence or metastases than imag-

size, not having a normal distribution of the data, and the

ing studies in some cases. The ROC curve analysis showed

short observation period. The most common type of lung can-

that follow-up CEA levels can be a potential predictor of

cer identified during the early study period was squamous

cancer recurrence or metastasis, and follow-up CEA levels

cell carcinoma, and compared to the present, regular health

were considered to be helpful in detecting early recurrence,

check-ups were less common in the past. Hence, most of our

which was not detected by imaging studies. At present, the

data were registered in the later study period and most pa-

serum CEA level is not included in the NCCN guidelines.

tients were in their early pathologic stage for lung adeno-

Nevertheless, follow-up CEA levels, as well as preoperative

carcinoma. Considering the homogenous nature of our data,

CEA levels, can be helpful prognostic indicators in patients

the results were statistically significant and comparable to

who undergo resections for lung adenocarcinoma [12,13].

those of the other large-scale studies even though our study

Previous studies have also reported that the independent prog-

enrolled a relatively small number of patients and the patients

nostic factors of the 5-year DFS after surgery are as follows:

were not evenly distributed with respect to their pathologic

the pathologic stage, neoadjuvant and adjuvant therapy, differ-

stage (IA in 94, IB in 35, IIA in 12, IIB in 3, and IIIA in

entiation, vascular invasion, lymphatic invasion, preoperative

14). A future analysis of a larger number of cases for a lon-

CEA levels, and the extent of resection and gene mutation

ger period may be able to provide more reliable results. The

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Carcinoembryonic Antigen in Lung Cancer

third limitation is the lack of strict standardization of the

REFERENCES

CEA measurement algorithm. To overcome the absence of a definite algorithm, we defined each CEA level strictly according to the time. Therefore, only 158 of 305 patients could be included in the present study. The fourth limitation is the extent of resection. There was no definite indication for limited resections, and limited resections were mainly performed in high-risk patients in their early stage, making the number of designated patients relatively small. In spite of this, the preoperative CEA levels did not differ according to the extent of the resections in this study. Further, there was no significant difference in the prognosis between patients who underwent limited resection and lobectomy, or more extensive resection. Nevertheless, this study shows strong evidence of associations between serum CEA levels and disease status and prognosis after surgery. Therefore, the measurement of CEA levels may improve the evaluation of the current status and prognosis after surgery for lung adenocarcinoma patients. Moreover, individualized treatment for lung adenocarcinoma can be achieved. In conclusion, although the CEA level cannot be a preoperative screening test for lung adenocarcinoma due to the low incidence of CEA elevation, the preoperative CEA levels and follow-up CEA levels can be used as prognostic factors for lung adenocarcinoma after surgery. The follow-up CEA level can be a useful tool for detecting early recurrence undetected by postoperative imaging studies. Therefore, preoperative and postoperative follow-up CEA levels may be helpful for providing personalized evaluation and management.

CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS This study was supported by a Grant of the Samsung Vein Clinic Network (Daejeon, Anyang, Cheongju, Cheonan; Fund No.KTCS04-034).

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